Neuromechanical basis of baroreceptor function

描述（由申请人提供）：动脉压力感受器（BR）对心率和血压的可靠神经控制至关重要。量化这些压力感受器的特性以及BR功能和功能障碍的反射性后果的数据是广泛的。对压力反射功能障碍和心血管疾病如神经介导的晕厥、心律失常和高血压的实验解释具有重要的临床意义。与年龄相关的动脉壁特性变化与心血管压力反射障碍、血压变异性水平升高、对急性血流动力学挑战的反应能力受损以及心源性猝死风险增加密切相关（Monahan, 2007）。BR传感器本身代表了这些不同病理的基本功能交叉点，但缺乏对转导机制的明确解释。我们的工作假设是，微观解剖、细胞外组织基质、BR末端复合物的可兴奋神经膜和区域动脉壁组织都对由动脉压力动力学引起的局部微机械力的空间整合和转导做出了不同的功能贡献。我们的具体目标集中在有髓鞘和无髓鞘大鼠主动脉BR的神经力学特性上，因为这些特性可以通过三种互补的方法进行微观和宏观研究：1)共聚焦、电子和荧光显微镜结合免疫组织化学标记的蛋白质表达，以及限定BR末端的组织结构；2)细胞外记录主动脉BR纤维放电对计算机控制的动脉壁压力负荷的响应；3)将这些不同的显微镜和生物物理数据合成为机械感觉转导的神经和微观力学机制的综合计算模型，这些模型无法进行直接测试和测量。我们的初步结果表明：1)有髓鞘和无髓鞘纤维BR末端超微结构上分子识别离子通道拓扑分布的本质差异；2)BR神经元细胞体上表达的离子通道的最小补体可能是机械转导的神经源性机制的基础；3)这些离子机制有助于但不能完全解释适应性等动态特性。放电阈值的迟滞和复位。这种实验和计算相结合的策略使我们对基底膜上的BR传入、周围组织基质内的弹性蛋白和胶原纤维以及机械转导的神经整合过程的结构-功能关系有了更深入的生物物理理解。正如我们最近所证明的那样（Feng et al., 2007），这种综合方法可以导致对急性心血管疾病的新见解，众所周知，急性心血管疾病通过激活动脉机械感受器来调用自主反射。公共卫生相关性：为了使大脑适当地控制心脏，它必须不断地接收有关血压和心率的信息。这一应用涉及到与动脉压力传感器（压力感受器）相关的实验性生物工程研究，它为大脑提供了至关重要的信息。更详细地了解这些传感器如何正常工作，如何适应血压、心率和动脉状况的短期和长期变化（例如随着年龄的增长），将有助于医生在健康和疾病的情况下更好地管理心脏功能。

DESCRIPTION (provided by applicant): Arterial baroreceptors (BR) are essential for reliable neural control of heart rate and blood pressure. The data quantifying the properties of these pressoreceptors and the reflexogenic consequences of BR function and dysfunction are extensive. Experimental interpretations of baroreflex dysfunction and cardiovascular pathologies such as neurally mediated syncope, dysrhythmias and hypertension are of significant clinical importance. Age related changes in arterial wall properties strongly correlate with cardiovagal baroreflex impairment, increased levels of blood pressure variability, an impaired ability to respond to acute hemodynamic challenges and increased risk of sudden cardiac death (Monahan, 2007). The BR sensor itself represents an essential functional intersection across these diverse pathologies and yet a clarifying explanation of the transduction machinery is lacking. Our working hypothesis is that the microanatomy, extracellular tissue matrix, excitable neural membrane of the BR terminal complex and regional arterial wall tissues all make functionally distinct contributions to the spatial integration and transduction of localized micromechanical forces arising from arterial pressure dynamics. Our specific aims center upon the neuromechanical properties of myelinated and unmyelinated rat aortic BR as these are accessible for both micro- and macroscopic study using three complementary methodologies: 1) confocal, electron and fluorescent microscopy in conjunction with immunohistochemical labeling of protein expression within, and the tissue constructs that circumscribe, the BR terminal ending, 2) extracellular recording of aortic BR fiber discharge in response to computer controlled pressure loading of the arterial wall and 3) synthesis of these disparate microscopy and biophysical data into comprehensive computational models of the neural and micromechanical mechanisms of mechanosensory transduction that are inaccessible for direct testing and measurement. Our preliminary results illustrate: 1) essential differences between the topological distribution of molecularly identified ion channels along the ultrastructure of BR terminals with myelinated and unmyelinated fibers, 2) a minimum complement of the ion channels expressed at the cell body of BR neurons may underlie the neurogenic mechanisms of mechanotransduction and 3) that these ionic mechanisms contribute to, but cannot entirely account for, such dynamic properties as adaptation, hysteresis and resetting of discharge threshold. This combined experimental and computational strategy is producing a more biophysical understanding of the structure-function relationships associated with BR afferents relative to the basement membrane about the terminal ending, the elastin and collagen fibers within the surrounding tissue matrix as well as the neuro-integrative processes of mechanotransduction. As we recently demonstrated (Feng et al., 2007), this integrative approach can lead to new insights concerning acute cardiovascular pathologies that are well known to invoke autonomic reflexes through activation of arterial mechanoreceptors. PUBLIC HEALTH RELEVANCE: In order for the brain to properly control the heart it must continually receive information concerning blood pressure and heart rate. This application involves experimental bioengineering research related to the arterial pressure sensors (baroreceptors) that provide this critically important information to the brain. A more detailed understanding of how these sensors normally work and adapt to short and long term changes in blood pressure, heart rate and the condition of the arteries (e.g. with aging) will help physicians better manage heart function under conditions of health and disease.